Journal of Food and Drug Analysis (JFDA)
【Update Date:2022-09-15】unit:
Diallyl disulfide inhibits proliferation, epithelial—mesenchymal transition, and invasion through RORα-mediated downregulation of Wnt1/β-catenin pathway in gastric cancer cells
Jian Sua,b,1, Hui Heb,d,1, Yu-Kun Lib,1, Hong Xiab, Fang Liub, Ying Zengb, Xi Zengb, Hui Lingb, Bo Sub,c,*, Qi Sub,d,* *
a Department of Pathology, Second Affiliated Hospital, University of South China, Chang Sheng Xi Avenue 28, Hengyang, Hunan 421001, China
b Hunan Province Key Laboratory of Cancer Cellular and Molecular Pathology, Cancer Research Institute, Hengyang Medical School, University of South China, Chang Sheng Xi Avenue 28, Hengyang, Hunan 421001, China
c Institute of Pharmacy and Pharmacology, School of Pharmacy, Hengyang Medical School, University of South China, Chang Sheng Xi Avenue 28, Hengyang, Hunan 421001, China
d Clinical Anatomy & Reproductive Medicine Application Institute, Hengyang Medical School, University of South China, Chang Sheng Xi Avenue 28, Hengyang, Hunan 421001, China
Overactivation of Wnt/β-catenin pathway due to dysfunction of retinoid-related orphan receptor α (RORα) is related to cancer development and progression. We previously discovered that diallyl disulfide (DADS), one of active components of garlic, increases RORα expression in gastric cancer (GC) cells by using proteomic approaches. This study revealed that DADS treatment resulted in reducing Wnt1, β-catenin, TCF-4, intranuclear β-catenin and p-β-catenin levels in GC cells, concomitant with the decreased expression of β-catenin target genes (Axin, c-Jun, and c-Myc). RORα overexpression augmented DADS-induced downregulation of Wnt1/β-catenin pathway, G2/M phase arrest, and cell growth inhibition in vitro and in vivo. However, knockdown of RORα attenuated these effects of DADS. Intriguingly, DADS induced an increase in the binding of RORα to β-catenin, which may lead to reduction of β-catenin phosphorylation and nuclear translocation. This interplay modulated by DADS may affect β-catenin target gene expression for that the opposite results were observed in DADS-treated RORα knockdown and overexpression cells. DADS caused a decrease in vimentin, snail and MMP-9, as well as an increase in E-cadherin and TIMP3 expression, restricting epithelial‑mesenchymal transition (EMT), migration, and invasion. These effects of DADS were weakened simultaneously when the suppression of DADS on the Wnt1/β-catenin pathway was resisted by knockdown of RORα. In contrast, overexpression of RORα enhanced the effects of DADS. Therefore, RORα-mediated downregulation of Wnt1/β-catenin pathway could undertake an important role in anticancer activity of DADS against GC cell proliferation, EMT, migration, and invasion.
Keywords: Diallyl disulfide; Gastric cancer cell epithelial-mesenchymal transition; Proliferation; RORα; Wnt/β-catenin pathway
https://doi.org/10.38212/2224-6614.3424
(https://www.jfda-online.com/journal/vol30/iss3/12)